Immune senescence is a pooriy understood phenomenon characteristic of the immune response of the aged. In aged humans (and mice), this immune disregulafion is characterized by poor a prognosis following traumatic injury or infection, a weak response to experimentally introduced immune sfimulafion, but an elevated level of many pro-inflammatory cytokines. We have found that Drosophila melanogaster also exhibits a similar immune senescence. In particular, aged flies have elevated levels of anfimicrobial pepfides but respond pooriy to immune challenge. The innate immune recognition and signaling systems that control pro-inflammatory cytokine and antimicrobial peptide production are highly conserved between insects and mammals. Therefore, the detailed examinafion of immune senescence in flies will lead to new insights into similar processes in humans. We hypothesize that aged files have a weakened immune response, which leads to persistent infections and elevated levels of antimicrobial peptides. This will be directly examined in Aim 1. We further propose two possible mechanisms by which the immune response is modulated by aging. In Aim 2, we will investigate in molecular detail the possibility that the Insulin/ Insulin like Signaling, which is known to be a critical modulator of lifespan, directly affect immunity. In Aim 3, we will broaden this approach and use a fonA/ard genetic screen to identify novel pathways affecting the progression of innate immune dysfunction with age.